State breastfeeding worksite statutes.…breastfeeding rates…and.….
State worksite breastfeeding statutes are thought to play a role in increasing rates of breastfeeding duration, which remain below Healthy People 2010 goals. As of 2010 24 states including the District of Columbia had such worksite statutes. Of these only 18 required both break time and a site. This preliminary analysis assessed if infants born in states with worksite breastfeeding statutes had longer breastfeeding duration. Using the 2009 National Immunization Survey we analyzed infants comparing breastfeeding duration at 6 months with type of worksite breastfeeding statute in place, while adjusting for year enacted and other state characteristics (years since founding of state breastfeeding coalition, breastfeeding supportive hospital practices). Other covariates included maternal and infant characteristics. Only those infants whose mothers were at least 18 years old and who had not changed state of residence since birth were included (n=16,145). Although requiring a site and/or break time for breastfeeding increased the likelihood of breastfeeding at 6 months (odds ratio, 1.20; 95% confidence interval, 1.07-1.35; p=0.002), after accounting for other factors this relationship remained positive but was not significant (adjusted odd ratio, 1.07; 95% confidence interval, 0.92-1.24). Because all mothers, not just those in or returning to the workforce, were included in the analysis this relationship could be underestimated. Breastfeeding at 6 months was associated with being from a state that had had a breastfeeding coalition for a longer period of time (adjusted odds ratio, 1.25; 95% confidence interval, 1.04-1.49; p<0001). State worksite breastfeeding statutes alone may not directly affect breastfeeding duration. Analysis of breastfeeding duration using the multiple levels of the social-ecological model is a potentially useful approach to understanding the impact of state breastfeeding statutes. The impact of state breastfeeding coalitions warrants further study.


STRICTA: is it time to do more?
In order to facilitate the completeness and transparency of reporting on randomized controlled trials undertaken using acupuncture interventions, a consensus group of international experts developed the Standards for Reporting Interventions in Controlled Trials of Acupuncture (STRICTA) in 2002. This reporting guideline was updated in 2010, and was applicable to a broader range of acupuncture research, including uncontrolled trials and case reports. Subsequent evaluations have noted limitations on the impact of STRICTA in the reporting quality of acupuncture trials, and the description of acupuncture details remains poor. Thus improvement in the efficacy of the STRICTA guidelines is called for. We explored the STRICTA guidelines from four aspects, including the development procedure, validity assessment, endorsement and adherence, and citation situation. Based upon these findings, we provided five potential suggestions for further development of STRICTA. STRICTA are valid reporting guidelines based on robust methodology and scientific content. However specific implementation strategies including: updating the STRICTA checklist; improving the STRICTA reporting efficiency; consistency with implementing the "Instructions for authors" for journals; establishing global STRICTA research centers; and expanding the STRICTA website, are needed. Such strategies will improve their utilization and impact positively on the quality of reporting on acupuncture research outcomes.


Comprehensive analysis of RNA-seq data reveals the complexity of the transcriptome in Brassica rapa.
The species Brassica rapa (2n=20, AA) is an important vegetable and oilseed crop, and serves as an excellent model for genomic and evolutionary research in Brassica species. With the availability of whole genome sequence of B. rapa, it is essential to further determine the activity of all functional elements of the B. rapa genome and explore the transcriptome on a genome-wide scale. Here, RNA-seq data was employed to provide a genome-wide transcriptional landscape and characterization of the annotated and novel transcripts and alternative splicing events across tissues. RNA-seq reads were generated using the Illumina platform from six different tissues (root, stem, leaf, flower, silique and callus) of the B. rapa accession Chiifu-401-42, the same line used for whole genome sequencing. First, these data detected the widespread transcription of the B. rapa genome, leading to the identification of numerous novel transcripts and definition of 5'/3' UTRs of known genes. Second, 78.8% of the total annotated genes were detected as expressed and 45.8% were constitutively expressed across all tissues. We further defined several groups of genes: housekeeping genes, tissue-specific expressed genes and co-expressed genes across tissues, which will serve as a valuable repository for future crop functional genomics research. Third, alternative splicing (AS) is estimated to occur in more than 29.4% of intron-containing B. rapa genes, and 65% of them were commonly detected in more than two tissues. Interestingly, genes with high rate of AS were over-represented in GO categories relating to transcriptional regulation and signal transduction, suggesting potential importance of AS for playing regulatory role in these genes. Further, we observed that intron retention (IR) is predominant in the AS events and seems to preferentially occurred in genes with short introns. The high-resolution RNA-seq analysis provides a global transcriptional landscape as a complement to the B. rapa genome sequence, which will advance our understanding of the dynamics and complexity of the B. rapa transcriptome. The atlas of gene expression in different tissues will be useful for accelerating research on functional genomics and genome evolution in Brassica species.


Fasciola hepatica infection reduces Mycobacterium bovis burden and mycobacterial uptake and suppresses the pro-inflammatory response.
Bovine tuberculosis (BTB), caused by Mycobacterium bovis, has an annual incidence in cattle of 0.5% in the Republic of Ireland and 4.7% in the UK, despite long-standing eradication programmes being in place. Failure to achieve complete eradication is multifactorial, but the limitations of diagnostic tests are significant complicating factors. Previously, we have demonstrated that Fasciola hepatica infection, highly prevalent in these areas, induced reduced sensitivity of the standard diagnostic tests for BTB in animals co-infected with F. hepatica and M. bovis. This was accompanied by a reduced M. bovis-specific Th1 immune response. We hypothesized that these changes in co-infected animals would be accompanied by enhanced growth of M. bovis. However, we show here that mycobacterial burden in cattle is reduced in animals co-infected with F. hepatica. Furthermore, we demonstrate a lower mycobacterial recovery and uptake in blood monocyte-derived macrophages (MDM) from F. hepatica-infected cattle which is associated with suppression of pro-inflammatory cytokines and a switch to alternative activation of macrophages. However, the cell surface expression of TLR2 and CD14 in MDM from F. hepatica-infected cattle is increased. These findings reflecting the bystander effect of helminth-induced downregulation of pro-inflammatory responses provide insights to understand host-pathogen interactions in co-infection.


Ethanol inhibition of constitutively open N-methyl-D-aspartate receptors.
N-Methyl-D-aspartate (NMDA) receptors gate a slow and calcium-rich component of the postsynaptic glutamate response. Like all ionotropic glutamate receptors, NMDA subunits contain a highly conserved motif (SYTANLAAF) in the transmembrane (TM) 3 domain that is critically involved in channel gating. Mutation of an alanine in this domain (A7; underlined above) results in constitutively open receptors that show reduced sensitivity to several allosteric modulators. In this study, we examined the effects of ethanol, a substance that inhibits NMDA currents via an unknown mechanism, on tonically active NMDA receptors expressed in human embryonic kidney 293 cells. Ethanol (100 mM) inhibited currents from GluN1(A7R)/GluN2A and GluN1(A7R)/GluN2B receptors by approximately 50%, whereas those from GluN1/GluN2B(A7R) receptors were reduced by less than 10%. In cysteine-substituted GluN1 and GluN2 A7 mutants, estimated ethanol IC₅₀ values for agonist-gated currents were 101, 117, 103, and 69 mM for GluN1(A7C)/GluN2A, GluN1(A7C)/GluN2B, GluN1/GluN2A(A7C), and GluN1/GluN2B(A7C) receptors, respectively. After exposure to the thiol-modifying reagent 2-(trimethylammonium)ethyl methanethiosulfonate (MTSET), A7C mutants showed robust agonist-independent currents and reduced sensitivity to ethanol (IC₅₀ values of 371, 256, 715, and 958 mM, respectively, as above). In contrast, cysteine modification of the ligand-binding domain resulted in constitutively open receptors that showed robust ethanol inhibition. Ethanol inhibition of MTSET-treated GluN1(A7C) receptors was further reduced by TM3/TM4 mutations previously shown to reduce ethanol sensitivity of agonist-gated receptors. Overall, these results show that ethanol affects NMDA receptor function at a site distal from agonist binding and appears to exert greater effects via perturbation of GluN2 subunits.


Measurement of model coefficients of skin sympathetic vasoconstriction.
Many researchers have already attempted to model vasoconstriction responses, commonly using the mathematical representation proposed by Stolwijk (1971 NASA Contractor Report CR-1855 (Washington, DC: NASA)). Model makers based the parameter values in this formulation either on estimations or by attributing the difference between their passive models and measurement data fully to thermoregulation. These methods are very sensitive to errors. This study aims to present a reliable method for determining physiological values in the vasoconstriction formulation. An experimental protocol was developed that enabled us to derive the local proportional amplification coefficients of the toe, leg and arm and the transient vasoconstrictor tone. Ten subjects participated in a cooling experiment. During the experiment, core temperature, skin temperature, skin perfusion, forearm blood flow and heart rate variability were measured. The contributions to the normalized amplification coefficient for vasoconstriction of the toe, leg and arm were 84%, 11% and 5%, respectively. Comparison with relative values in the literature showed that the estimated values of Stolwijk and the values mentioned by Tanabe et al (2002 Energy Build. 34 637-46) were comparable with our measured values, but the values of Gordon (1974 The response of a human temperature regulatory system model in the cold PhD Thesis University of California, Santa Barbara) and Fiala et al (2001 Int. J. Biometeorol. 45 143159) differed significantly. With the help of regression analysis a relation was formulated between the error signal of the standardized core temperature and the vasoconstrictor tone. This relation was formulated in a general applicable way, which means that it can be used for situations where vasoconstriction thresholds are shifted, like under anesthesia or during motion sickness.


The potential effectiveness of essential oils as a treatment for headlice, Pediculus humanus capitis.
Essential oils of aniseed, cinnamon leaf, red thyme, tea tree, peppermint, nutmeg, rosemary, and pine were tested in vitro against lice, Pediculus humanus. All the oils except for rosemary and pine were found to be effective in the laboratory when applied in an alcoholic solution and followed by a rinse the following morning in an essential oil/vinegar/water mixture. Peppermint and nutmeg were only used as a blend rather than as individual oils. Problems of solubility and toxicity are discussed, as are possible mechanisms of action. Phenols, phenolic ethers, ketones, and oxides (1,8-cineole) appear to be the major toxic components of these essential oils when used on lice. Aldehydes and sesquiterpenes may also play a role.


Divergent roles of herbivory in eutrophying forests.
Ungulate populations are increasing across Europe with important implications for forest plant communities. Concurrently, atmospheric nitrogen (N) deposition continues to eutrophicate forests, threatening many rare, often more nutrient-efficient, plant species. These pressures may critically interact to shape biodiversity as in grassland and tundra systems, yet any potential interactions in forests remain poorly understood. Here, we combined vegetation resurveys from 52 sites across 13 European countries to test how changes in ungulate herbivory and eutrophication drive long-term changes in forest understorey communities. Increases in herbivory were associated with elevated temporal species turnover, however, identities of winner and loser species depended on N levels. Under low levels of N-deposition, herbivory favored threatened and small-ranged species while reducing the proportion of non-native and nutrient-demanding species. Yet all these trends were reversed under high levels of N-deposition. Herbivores also reduced shrub cover, likely exacerbating N effects by increasing light levels in the understorey. Eutrophication levels may therefore determine whether herbivory acts as a catalyst for the "N time bomb" or as a conservation tool in temperate forests.


Elevated Metabolites of Steroidogenesis and Amino Acid Metabolism in Preadolescent Female Children With High Urinary Bisphenol A Levels: A High-Resolution Metabolomics Study.
Health risks associated with bisphenol A (BPA) exposure are controversially highlighted by numerous studies. High-resolution metabolomics (HRM) can confirm these proposed associations and may provide a mechanistic insight into the connections between BPA exposure and metabolic perturbations. This study was aimed to identify the changes in metabolomics profile due to BPA exposure in urine and serum samples collected from female and male children (n = 18) aged 7-9. Urine was measured for BPA concentration, and the children were subsequently classified into high and low BPA groups. HRM, coupled with Liquid chromatography-mass spectrometry/MS, followed by multivariate statistical analysis using MetaboAnalyst 3.0, were performed on urine to discriminate metabolic profiles between high and low BPA children as well as males and females, followed by further validation of our findings in serum samples obtained from same population. Metabolic pathway analysis showed that biosynthesis of steroid hormones and 7 other pathways-amino acid and nucleotide biosynthesis, phenylalanine metabolism, tryptophan metabolism, tyrosine metabolism, lysine degradation, pyruvate metabolism, and arginine biosynthesis-were affected in high BPA children. Elevated levels of metabolites associated with these pathways in urine and serum were mainly observed in female children, while these changes were negligible in male children. Our results suggest that the steroidogenesis pathway and amino acid metabolism are the main targets of perturbation by BPA in preadolescent girls.


The database for reaching experiments and models.
Reaching is one of the central experimental paradigms in the field of motor control, and many computational models of reaching have been published. While most of these models try to explain subject data (such as movement kinematics, reaching performance, forces, etc.) from only a single experiment, distinct experiments often share experimental conditions and record similar kinematics. This suggests that reaching models could be applied to (and falsified by) multiple experiments. However, using multiple datasets is difficult because experimental data formats vary widely. Standardizing data formats promises to enable scientists to test model predictions against many experiments and to compare experimental results across labs. Here we report on the development of a new resource available to scientists: a database of reaching called the Database for Reaching Experiments And Models (DREAM). DREAM collects both experimental datasets and models and facilitates their comparison by standardizing formats. The DREAM project promises to be useful for experimentalists who want to understand how their data relates to models, for modelers who want to test their theories, and for educators who want to help students better understand reaching experiments, models, and data analysis.


Concomitant Temperature Stress and Immune Activation may Increase Mortality Despite Efficient Clearance of an Intracellular Bacterial Infection in Atlantic Cod.
The environmental temperature has profound effects on biological systems of marine aquatic organisms and plays a critical role in species distribution and abundance. Particularly during the warmer seasons, variations in habitat temperature may introduce episodes of stressful temperatures which the organisms must adapt to and compensate for to maintain physiological homeostasis. The marine environment is changing and predicted raises in water temperatures will affect numerous marine species. Translocation of pathogens follow migration of species and alternations in physical environmental parameters may have influence upon the virulence of pathogens, as well as the hosts immune responses. While pathogenicity of many true pathogens is expected to increase following climate induced temperature stress, the impact from environmental stressors on the occurrence and severity of opportunistic infections is unknown. Here we describe how thermal stress in the cold-water species Atlantic cod influenced the fish immune responses against an opportunistic intracellular bacterium. Following experimental infection with Brucella pinnipedialis at normal water temperature (6°C) and sub-optimal temperature (15°C), cod cleared the intracellular bacteria more rapidly at the highest temperature. The overall immune response was faster and of higher amplitude at 15°C, however, a significant number of cod died at this temperature despite efficient clearance of infection. An increased growth rate not affected by infection was observed at 15°C, confirming multiple energy demanding processes taking place. Serum chemistry suggested that general homeostasis was influenced by both infection and increased water temperature, highlighting the cumulative stress responses (allostatic load) generated by simultaneous stressors. Our results suggest a trade-off between resistance and tolerance to survive infection at sub-optimal temperatures and raise questions concerning the impact of increased water temperatures on the energetic costs of immune system activation in aquatic ectotherms.


The technological imperative in tuberculosis care and prevention in Vietnam.
A monocausal bacteriological understanding of infectious disease orients tuberculosis control efforts towards antimicrobial interventions. A bias towards technological solutions can leave multistranded public health and social interventions largely neglected. In the context of globalising biomedical approaches to infectious disease control, this ethnography-inspired review article reflects upon the implementation of rapid diagnostic technology in low- and middle-income countries. Fieldwork observations in Vietnam provided a stimulus for a critical review of the global rollout of tuberculosis diagnostic technology. To address local needs in tuberculosis control, health managers in resource-poor settings are readily cooperating with international donors to deploy novel diagnostic technologies throughout national tuberculosis programme facilities. Increasing investment in new diagnostic technologies is predicated on the supposition that these interventions will ameliorate disease outcomes. However, suboptimal treatment control persists even when accurate diagnostic technologies are available, suggesting that promotion of singular technological solutions can distract from addressing systemic change, without which disease susceptibility, propagation of infection, detection gaps, diagnostic delays, and treatment shortfalls persist.


Comprehension problems in children with specific language impairment: literal and inferential meaning.
A group of 61 schoolchildren with specific language impairment (SLI) was compared with a control group on a comprehension task, in which the child was questioned about a story that had been presented either orally or as a series of pictures. Half the questions were literal, requiring the child to provide a detail that had been mentioned or shown explicitly in the story. The remainder required the child to make an inference about what had not been directly shown or stated. SLI children were impaired on this task, even after taking into account "comprehension age," as assessed on a multiple-choice test. However, the effects of mode of presentation and question type were similar for control and SLI groups. Children who fitted the clinical picture of semantic-pragmatic disorder had lower scores than other SLI children on this task. In addition, they were more prone to give answers that suggested they had not understood the question. However, as with the other SLI children, there was no indication that they had disproportionate difficulty with inferential questions. It is concluded that SLI children are impaired in constructing an integrated representation from a sequence of propositions, even when such propositions are presented nonverbally.


Observatons on the growth and metabolic functions of cultured cells derived from human adipose tissue.
The growth and metabolic activity of cultured cells derived from human adipose tissue (CAT cells) were studied and compared to cultured skin fibroblasts. The morphological appearance of the CAT cells was distinctly different from that of fibroblasts. The growth rate of CAT cells as measured by 3H-thymidine incorporation was much slower than the fibroblast growth rate. Cultured CAT cells synthesized significantly 14C-glucose, while fibroblast cultures had a higher metabolic rate as measured by CO2 production. Insulin stimulated 3H-thymidine incorporation in both CAT and fibroblast cultures. The CAT cells did not show a consistent insulin response of lipid or CO2 production, but this may be a reflection of donor age or nutritional status. Even though the CAT cell may be a type of stromal cell peculiar to adipose tissue rather than a preadipocyte or adipocyte, it may prove useful in studies of human obesity.


[Positioning trauma in anesthesia and surgical intensive care medicine (2)].
Specific modes of positioning are essential for successful surgery. These are again critically assessed in this final part of our review. Technically correct execution can minimize the risk of damage caused by positioning, although the possibility of damage still exists. First of all, the position on the fracture table is discussed. Great care must be taken concerning the perineal post and leg holder. In the lateral decubitus position, the correct positioning of head and spine as well as that of the lower arm are of great importance. When using the Trendelenburg and reverse Trendelenburg position, the effect on the cardiopulmonary system and the intracranial pressure must to be taken into consideration. Prone position and its modifications (i.e. tuck position) demand diligent care concerning the positioning of the head. There must be absolutely no bulbus compression and the abdominal wall should not be under pressure. While employing the sitting position, the patient should be adequately monitored so that venous air embolism can be recognized and treated as soon as possible. Because of the increased occurrence of grave complications, the sitting position should be used only if this is absolutely necessary.


Acylhydrazine-based reticular hydrogen bonds enable robust, tough, and dynamic supramolecular materials.
Supramolecular materials are widely recognized among the most promising candidates for future generations of sustainable plastics because of their dynamic functions. However, the weak noncovalent cross-links that endow dynamic properties usually trade off materials' mechanical robustness. Here, we present the discovery of a simple and robust supramolecular cross-linking strategy based on acylhydrazine units, which can hierarchically cross-link the solvent-free network of poly(disulfides) by forming unique reticular hydrogen bonds, enabling the conversion of soft into stiff dynamic material. The resulting supramolecular materials exhibit increase in stiffness exceeding two to three orders of magnitude compared to those based on the hydrogen-bonding network of analogous carboxylic acids, simultaneously preserving the repairability, malleability, and recyclability of the materials. The materials also show high adhesion strength on various surfaces while allowing multiple surface attachment cycles without fatigue, illustrating a viable approach how robustness and dynamics can be merged in future material design.


A curated gluten protein sequence database to support development of proteomics methods for determination of gluten in gluten-free foods.
The unique physiochemical properties of wheat gluten enable a diverse range of food products to be manufactured. However, gluten triggers coeliac disease, a condition which is treated using a gluten-free diet. Analytical methods are required to confirm if foods are gluten-free, but current immunoassay-based methods can unreliable and proteomic methods offer an alternative but require comprehensive and well annotated sequence databases which are lacking for gluten. A manually a curated database (GluPro V1.0) of gluten proteins, comprising 630 discrete unique full length protein sequences has been compiled. It is representative of the different types of gliadin and glutenin components found in gluten. An in silico comparison of their coeliac toxicity was undertaken by analysing the distribution of coeliac toxic motifs. This demonstrated that whilst the α-gliadin proteins contained more toxic motifs, these were distributed across all gluten protein sub-types. Comparison of annotations observed using a discovery proteomics dataset acquired using ion mobility MS/MS showed that more reliable identifications were obtained using the GluPro V1.0 database compared to the complete reviewed Viridiplantae database. This highlights the value of a curated sequence database specifically designed to support the proteomic workflows and the development of methods to detect and quantify gluten. We have constructed the first manually curated open-source wheat gluten protein sequence database (GluPro V1.0) in a FASTA format to support the application of proteomic methods for gluten protein detection and quantification. We have also analysed the manually verified sequences to give the first comprehensive overview of the distribution of sequences able to elicit a reaction in coeliac disease, the prevalent form of gluten intolerance. Provision of this database will improve the reliability of gluten protein identification by proteomic analysis, and aid the development of targeted mass spectrometry methods in line with Codex Alimentarius Commission requirements for foods designed to meet the needs of gluten intolerant individuals.


Guidelines for data and safety monitoring for clinical trials not requiring traditional data monitoring committees.
This is a commissioned report by a writing committee formed by the Society for Clinical Trials. The committee was formed with the objectives of 1) reviewing data monitoring guidelines for confirmatory (phase III) trials published by the National Institutes of Health, US Food and Drug Administration, Veterans Administration, and the International Conference on Harmonisation and 2) proposing corresponding guidelines for exploratory clinical trials (ie, most phase I and phase II trials and others not requiring a fully independent data monitoring committee). These trials typically involve fewer subjects and are of shorter duration than phase III trials. Nevertheless there are safety concerns, especially because these are often the first human trials for a new intervention. Recommendations are given for appropriate elements of a data monitoring plan, decision criteria for institution of a data monitoring committee (DMC), and critical elements for a DMC to consider in exploratory trials. Review and approval of data monitoring plans are suggested to fall under Institutional Review Board purview. Forming a committee with all the characteristics of a traditional phase III trial monitoring committee may be warranted for a small fraction of exploratory trials. Such a panel could consist of both trial investigators and outside members. The paper concludes with examples of data and safety monitoring practice from the University of Wisconsin Comprehensive Cancer Center and the AIDS Clinical Trials Groups.


[Evaluation of primary care from the perspective of users: adaptation of the EUROPEP instrument for major Brazilian urban centers].
Satisfaction with health care is a multidimensional concept that considers aspects such as access, organization and professional-user interaction. The aim of this study was to adapt and apply an instrument in the Family Health Strategy (FHS) to assess user satisfaction with Primary Health Care (PHC) based on the European Task Force on Patient Evaluation of General Practice Care (EUROPEP), which refers to user satisfaction wth general and family medicine services. The instrument consists of five dimensions of satisfaction: relationship and communication, medical care, information and support, continuity and cooperation, and organization of services. The study was divided into phases: review and adjustment of the instrument and application to a representative sample of users of the FHS in Rio de Janeiro. The averages of the proportions of answers for each indicator were calculated to analyze the results. Relationship and communication between professionals and users received the best evaluation and Organization of Services eceived the worst appraisal. Regarding education level, good self-perceived health and more elderly were more satisfied. The instrument proved to be easy to apply, can be routinely used for monitoring of the FHS, and is a tool for the institutionalization of evaluation.


Innate Immunity to Spiral Ganglion Neuron Loss: A Neuroprotective Role of Fractalkine Signaling in Injured Cochlea.
Immune system dysregulation is increasingly being attributed to the development of a multitude of neurodegenerative diseases. This, in large part, is due to the delicate relationship that exists between neurons in the central nervous system (CNS) and peripheral nervous system (PNS), and the resident immune cells that aid in homeostasis and immune surveillance within a tissue. Classically, the inner ear was thought to be immune privileged due to the presence of a blood-labyrinth barrier. However, it is now well-established that both vestibular and auditory end organs in the inner ear contain a resident (local) population of macrophages which are the phagocytic cells of the innate-immune system. Upon cochlear sterile injury or infection, there is robust activation of these resident macrophages and a predominant increase in the numbers of macrophages as well as other types of leukocytes. Despite this, the source, nature, fate, and functions of these immune cells during cochlear physiology and pathology remains unclear. Migration of local macrophages and infiltration of bone-marrow-derived peripheral blood macrophages into the damaged cochlea occur through various signaling cascades, mediated by the release of specific chemical signals from damaged sensory and non-sensory cells of the cochlea. One such signaling pathway is CX3CL1-CX3CR1, or fractalkine (FKN) signaling, a direct line of communication between macrophages and sensory inner hair cells (IHCs) and spiral ganglion neurons (SGNs) of the cochlea. Despite the known importance of this neuron-immune axis in CNS function and pathology, until recently it was not clear whether this signaling axis played a role in macrophage chemotaxis and SGN survival following cochlear injury. In this review, we will explore the importance of innate immunity in neurodegenerative disease development, specifically focusing on the regulation of the CX3CL1-CX3CR1 axis, and present evidence for a role of FKN signaling in cochlear neuroprotection.


[Biomechanical problems of the maxillodental system in children].
The biomechanical regularities of the function of anatomic blocks of the maxillodental system were studied using mathematical simulation and mathematical models. The biological concept of the structure and biomechanics of human masticatory system is presented. Methods of rapid diagnosis, based on the anthropometric characteristics of the face, and a mathematical model of the function of the maxillodental system intended for the orthodontic treatment of maxillodental abnormalities in children have been developed.


Variability in measures of exhaled breath na, influence of pulmonary blood flow and salivary na.
The assessment of inflammatory markers and ions in exhaled breath condensate (EBC) is being utilized more frequently in diseases such as asthma and cystic fibrosis with marked variability in EBC measures, including those of exhaled Na(+). We sought to determine if variability in exhaled Na(+) was due to differences in pulmonary blood flow (PBF) or Na(+) in the mouth (salivary Na(+)). We measured exhaled Na(+) three times with coinciding sampling of salivary Na(+) and assessment of PBF (using acetylene rebreathing) in 13 healthy subjects (54% female, age = 27 ± 7 yrs., ht. = 172 ± 10 cm, wt. = 70 ± 21 kg, BMI = 22 ± 7 kg/m(2) mean ± SD). Exhaled Na(+) averaged 2.7 ± 1.2 mmol/l, and salivary Na(+) averaged 5.51 ± 4.58 mmol/l. The coefficients of variation across all three measures in all 13 subjects averaged 30% for exhaled Na(+) and 83% for salivary Na(+), within subjects the variability across the three measures averaged 30% for exhaled Na(+) and 38% for salivary Na(+). Across all three measures in all 13 subjects the relationship between PBF and exhaled Na(+) averaged 0.027 (P = 0.87), and the relationship between salivary Na(+) and exhaled Na(+) concentrations averaged 0.59 (P = 0.001). Also, we sought to determine the relationship between exhaled Na(+) and serum Na(+) in an addition 20 subjects. There was a moderate and significant relationship between serum Na(+) and exhaled Na(+) (r = 0.37, P = 0.04). These findings suggest there that the variability in exhaled Na(+) is caused, at least in part, by droplet formation from within the mouth as turbulent air passes through and that there is a flux of ions from the pulmonary blood into the airways.


Effects of a D-xylose preload with or without sitagliptin on gastric emptying, glucagon-like peptide-1, and postprandial glycemia in type 2 diabetes.
Macronutrient "preloads" can reduce postprandial glycemia by slowing gastric emptying and stimulating glucagon-like peptide-1 (GLP-1) secretion. An ideal preload would entail minimal additional energy intake and might be optimized by concurrent inhibition of dipeptidyl peptidase-4 (DPP-4). We evaluated the effects of a low-energy D-xylose preload, with or without sitagliptin, on gastric emptying, plasma intact GLP-1 concentrations, and postprandial glycemia in type 2 diabetes. Twelve type 2 diabetic patients were studied on four occasions each. After 100 mg sitagliptin (S) or placebo (P) and an overnight fast, patients consumed a preload drink containing either 50 g D-xylose (X) or 80 mg sucralose (control [C]), followed after 40 min by a mashed potato meal labeled with (13)C-octanoate. Blood was sampled at intervals. Gastric emptying was determined. Both peak blood glucose and the amplitude of glycemic excursion were lower after PX and SC than PC (P < 0.01 for each) and were lowest after SX (P < 0.05 for each), while overall blood glucose was lower after SX than PC (P < 0.05). The postprandial insulin-to-glucose ratio was attenuated (P < 0.05) and gastric emptying was slower (P < 0.01) after D-xylose, without any effect of sitagliptin. Plasma GLP-1 concentrations were higher after D-xylose than control only before the meal (P < 0.05) but were sustained postprandially when combined with sitagliptin (P < 0.05). In type 2 diabetes, acute administration of a D-xylose preload reduces postprandial glycemia and enhances the effect of a DPP-4 inhibitor.


The down-regulation of galectin-1 expression is a specific biomarker of arsenic toxicity.
Galectin-1 (GAL1) is known as a β-galactoside-binding protein that also can bind with arsenic to regulate cell functions. Using RNA interference technique, we investigated the possible mechanism involved in GAL1 modulation of arsenite-inhibited cell survival in 3T3 fibroblast and KB oral cancer cells. GAL1 gene knockdown significantly attenuated sodium arsenite (NaAsO(2)) and arsenic trioxide (As(2)O(3)) inhibition of cell survival. However, GAL1 gene knockdown did not alter the inhibition of cell survival by antimony chloride, cadmium chloride or nickel sulfate. These results suggested the GAL1 selectively affects particular types of heavy metal elements. Flow cytometric analysis indicated GAL1 gene knockdown also suppressed As(III)-stimulated levels of sub-G1 and G2/M growth arrest in both cells. Moreover, atomic absorption spectrophotometric results showed that GAL1 gene knockdown reduced the total arsenic accumulation of both cells after the NaAsO(2) and As(2)O(3) treatment. These results suggested that GAL1 gene knockdown mediates the apoptotic effects of arsenic in 3T3 and KB cells via regulation of the cellular arsenic levels. We propose that down-regulation of GAL1 expression may be a useful and specific biomarker in assessing the toxicity of arsenic exposure.


Comparison of MR/ultrasound fusion-guided biopsy with ultrasound-guided biopsy for the diagnosis of prostate cancer.
Targeted magnetic resonance (MR)/ultrasound fusion prostate biopsy has been shown to detect prostate cancer. The implications of targeted biopsy alone vs standard extended-sextant biopsy or the 2 modalities combined are not well understood. To assess targeted vs standard biopsy and the 2 approaches combined for the diagnosis of intermediate- to high-risk prostate cancer. Prospective cohort study of 1003 men undergoing both targeted and standard biopsy concurrently from 2007 through 2014 at the National Cancer Institute in the United States. Patients were referred for elevated level of prostate-specific antigen (PSA) or abnormal digital rectal examination results, often with prior negative biopsy results. Risk categorization was compared among targeted and standard biopsy and, when available, whole-gland pathology after prostatectomy as the "gold standard." Patients underwent multiparametric prostate magnetic resonance imaging to identify regions of prostate cancer suspicion followed by targeted MR/ultrasound fusion biopsy and concurrent standard biopsy. The primary objective was to compare targeted and standard biopsy approaches for detection of high-risk prostate cancer (Gleason score ≥ 4 + 3); secondary end points focused on detection of low-risk prostate cancer (Gleason score 3 + 3 or low-volume 3 + 4) and the biopsy ability to predict whole-gland pathology at prostatectomy. Targeted MR/ultrasound fusion biopsy diagnosed 461 prostate cancer cases, and standard biopsy diagnosed 469 cases. There was exact agreement between targeted and standard biopsy in 690 men (69%) undergoing biopsy. Targeted biopsy diagnosed 30% more high-risk cancers vs standard biopsy (173 vs 122 cases, P < .001) and 17% fewer low-risk cancers (213 vs 258 cases, P < .001). When standard biopsy cores were combined with the targeted approach, an additional 103 cases (22%) of mostly low-risk prostate cancer were diagnosed (83% low risk, 12% intermediate risk, and 5% high risk). The predictive ability of targeted biopsy for differentiating low-risk from intermediate- and high-risk disease in 170 men with whole-gland pathology after prostatectomy was greater than that of standard biopsy or the 2 approaches combined (area under the curve, 0.73, 0.59, and 0.67, respectively; P < .05 for all comparisons). Among men undergoing biopsy for suspected prostate cancer, targeted MR/ultrasound fusion biopsy, compared with standard extended-sextant ultrasound-guided biopsy, was associated with increased detection of high-risk prostate cancer and decreased detection of low-risk prostate cancer. Future studies will be needed to assess the ultimate clinical implications of targeted biopsy. clinicaltrials.gov Identifier: NCT00102544.


The DREAM complex mediates GIST cell quiescence and is a novel therapeutic target to enhance imatinib-induced apoptosis.
Gastrointestinal stromal tumors (GIST) can be successfully treated with imatinib mesylate (Gleevec); however, complete remissions are rare and patients frequently achieve disease stabilization in the presence of residual tumor masses. The clinical observation that discontinuation of treatment can lead to tumor progression suggests that residual tumor cells are, in fact, quiescent and, therefore, able to re-enter the cell-division cycle. In line with this notion, we have previously shown that imatinib induces GIST cell quiescence in vitro through the APC(CDH1)-SKP2-p27(Kip1) signaling axis. Here, we provide evidence that imatinib induces GIST cell quiescence in vivo and that this process also involves the DREAM complex, a multisubunit complex that has recently been identified as an additional key regulator of quiescence. Importantly, inhibition of DREAM complex formation by depletion of the DREAM regulatory kinase DYRK1A or its target LIN52 was found to enhance imatinib-induced cell death. Our results show that imatinib induces apoptosis in a fraction of GIST cells while, at the same time, a subset of cells undergoes quiescence involving the DREAM complex. Inhibition of this process enhances imatinib-induced apoptosis, which opens the opportunity for future therapeutic interventions to target the DREAM complex for more efficient imatinib responses.


An intrinsic dimensionality estimator from near-neighbor information.
The intrinsic dimensionality of a set of patterns is important in determining an appropriate number of features for representing the data and whether a reasonable two- or three-dimensional representation of the data exists. We propose an intuitively appealing, noniterative estimator for intrinsic dimensionality which is based on nearneighbor information. We give plausible arguments supporting the consistency of this estimator. The method works well in identifying the true dimensionality for a variety of artificial data sets and is fairly insensitive to the number of samples and to the algorithmic parameters. Comparisons between this new method and the global eigenvalue approach demonstrate the utility of our estimator.


[Construction and expression of recombinant adenovirus containing human thymic stromal lymphopoietin gene].
To construct and express recombinant adenovirus bearing human thymic stromal lymphopoietin (TSLP) gene. TSLP gene amplified from human fetal lung cells was first cloned into eukaryotic expression vector pcDNA3.1, and then subcloned into shuttle vector pShuttle. The resultant plasmid was subsequently cotransformed into E. coli BJ5183 cells with adenoviral backbone plasmid pAdEasy-1. The recombinant adenovirus plasmid containing TSLP was digested with Pac I and transfected into HEK293 cells to package recombinant adenovirus particles. The TSLP gene of the recombinant virus was detected by PCR, and its expression was analyzed by Western blot. Recombinant adenovirus vector bearing human TSLP gene was constructed by homologous recombination in E.coli, and recombinant adenovirus was obtained by transfecting HEK293 cells with this infectious DNA. PCR test indicated that TSLP gene was successfully integrated into the adenoviral genome, and the titer of the recombinant Ad reached 1 x 10(11) pfu/L. Meanwhile, expression of TSLP in the infected Hela cells was confirmed by Western blot. The construction of recombinant adenovirus bearing human TSLP gene and its expression mediated by this adenovirus pave a foundation for the study on the biological function of this novel cytokine.


Genetic Characterization and Risk Stratification of Acute Myeloid Leukemia.
The most common acute leukemia in adults is acute myeloid leukemia (AML). The pathophysiology of the disease associates with cytogenetic abnormalities, gene mutations and aberrant gene expressions. At the molecular level, the disease manifests as changes in both epigenetic and genetic signatures. At the clinical level, two aspects of AML should be taken into account. First, the molecular changes occurring in the disease are important prognostic and predictive markers of AML. Second, use of novel therapies targeting these molecular changes. Currently, cytogenetic abnormalities and molecular alterations are the common biomarkers for the prognosis and choice of treatment for AML. Finding a panel of multiple biomarkers is a crucial diagnostic step for patient classification and serves as a prerequisite for individualized treatment strategies. Furthermore, the most important way of identifying relevant targets for new treatment approaches is defining specific patterns or a spectrum of driver gene mutations occurring in AML. Then, an algorithm can be established by the use of several biomarkers, to be used for personalized medicine. This review deals with molecular alterations, risk stratification, and relevant therapeutic decision-making in AML.


Rapidly occurring DNA excision repair events determine the biological expression of u.v.-induced damage in human cells.
We have developed a new assay which allows us to monitor the rates of repair of potentially lethal damage in u.v. (254 nm)-irradiated normal human skin fibroblasts. Using this assay we have shown that, in non-dividing cells, the majority of biologically effective excision repair is completed within 4 h following irradiation with low fluences of u.v. (1.5-6.0 J/m2). During this time, non-dividing cells removed only approximately 20% of the pyrimidine dimers induced in DNA by a u.v. fluence of 3.0 J/m2 as measured by the loss of u.v.-endonuclease-sensitive sites under identical repair conditions. The rates of repair of potentially lethal damage were also found to be independent of u.v. fluence over the range 1.5-6.0 J/m2 in non-dividing cells. In contrast, in cells irradiated in exponential growth with 1.5 J/m2, the rate of biologically effective repair was comparable with that observed in non-dividing cells but the efficiency of the repair process declined progressively with increase in u.v. fluence from 1.5 to 6.0 J/m2. Our data support the concept that the biological recovery of u.v.-irradiated cells depends on the preferential repair of damage in functionally important domains in the genome.


Effect of all-trans-retinoic acid on c-fms proto-oncogene [colony-stimulating factor 1 (CSF-1) receptor] expression and CSF-1-induced invasion and anchorage-independent growth of human breast carcinoma cells.
Abnormal expression of c-fms proto-oncogene, which encodes for the macrophage colony-stimulating factor-1 (CSF-1) receptor, has been observed in a variety of carcinomas of epithelial origin, including those of the breast. Here, we have investigated the effect of retinoic acid (RA), an important regulator of normal differentiation of mammary epithelial tissues, on the expression of the c-fms gene and CSF-1/CSF-1 receptor-induced invasion and anchorage-independent growth in breast carcinoma cells. We have demonstrated that all-trans-RA (atRA) significantly increases levels of c-fms transcripts in the estrogen receptor-negative but RA receptor alpha-positive breast carcinoma cell lines BT20 and SKBR3. The atRA-induced increase in fms transcript levels was completely abolished by RO41-5253, a synthetic RA receptor alpha antagonist. Our results indicate that atRA could enhance fms expression by up-regulating the activity of the first promoter of the fms gene. DNase I protection, mobility shift, and mutational analysis revealed that a potential activator protein 1 (AP-1) site in the first fms promoter sequence could mediate the observed atRA effect on fms transcription. Our results also showed that atRA, by itself and in the presence of CSF-1, can increase the ability of breast carcinoma cells to invade in vitro. Furthermore, we demonstrated that atRA is able to abolish the CSF-1-induced increase in anchorage-independent growth of breast carcinoma cells without affecting the anchorage-dependent growth. In summary, our findings suggest that retinoids may play conflicting roles throughout breast cancer progression, depending on the stage of cancer development. Although retinoids might suppress growth at the early stages of tumor formation, they might promote malignant transformation at later stages by stimulating the invasive capacity of certain cell variants in the breast tumor population.


The nuclear exosome contributes to autogenous control of NAB2 mRNA levels.
The RNA-processing exosome is a complex of riboexonucleases required for 3'-end formation of some noncoding RNAs and for the degradation of mRNAs in eukaryotes. The nuclear form of the exosome functions in an mRNA surveillance pathway that retains and degrades improperly processed precursor mRNAs within the nucleus. We report here that the nuclear exosome controls the level of NAB2 mRNA, encoding the nuclear poly(A)+-RNA-binding protein Nab2p. Mutations affecting the activity of the nuclear, but not the cytoplasmic, exosome cause an increase in the amount of NAB2 mRNA. Cis- and trans-acting mutations that inhibit degradation by the nuclear-exosome subunit Rrp6p result in elevated levels of NAB2 mRNA. Control of NAB2 mRNA levels occurs posttranscriptionally and requires a sequence of 26 consecutive adenosines (A26) in the NAB2 3' untranslated region, which represses NAB2 3'-end formation and sensitizes the transcript to degradation by Rrp6p. Analysis of NAB2 mRNA levels in a nab2-1 mutant and in the presence of excess Nab2p indicates that Nab2p activity negatively controls NAB2 mRNA levels in an A26- and Rrp6p-dependent manner. These findings suggest a novel regulatory circuit in which the nuclear exosome controls the level of NAB2 mRNA in response to changes in the activity of Nab2 protein.


Audiological issues and hearing loss among Veterans with mild traumatic brain injury.
We examined the prevalence, severity, etiology, and treatment of audiology problems among Operation Iraqi Freedom/Operation Enduring Freedom (OIF/OEF) Veterans with mild traumatic brain injury (TBI). A retrospective chart review was performed of 250 Veterans with mild TBI. Results of a comprehensive second-level mild TBI evaluation and subsequent visits to audiology were evaluated. We found the vast majority (87%) of Veterans reported some level of hearing disturbance and those involved in blast injuries reported a higher incidence of hearing disturbance than those with other injury etiologies. Audiology referrals were given to 75 Veterans and 37 attended. At this visit, Veterans reported tinnitus (75.7%) and hearing loss (59.8%). Nearly half (48.6%) of Veterans were diagnosed with conductive hearing loss, sensorineural hearing loss, or central auditory dysfunction. An additional 24.3% of Veterans had subclinical levels of auditory dysfunction. Our study has highlighted the increased prevalence of hearing loss among OIF/OEF Veterans and, thus, the need for appropriate referrals and treatment. Strategies to address perceived stigma associated with hearing loss may increase attendance at follow-up visits. Additionally, while only a third of audiograms were found to be abnormal, advanced testing resulted in a significant percentage of our population being diagnosed with auditory dysfunction.


Lipid micelles packaged with semiconducting polymer dots as simultaneous MRI/photoacoustic imaging and photodynamic/photothermal dual-modal therapeutic agents for liver cancer.
Incorporating multiple imaging modalities and simultaneous therapeutic functions together into one single nano-formulation is of great importance for developing high-performance clinical-translatable theranostic agents. Herein, we fabricated multifunctional lipid-micelles incorporated with semiconducting polymer dots and a photosensitizer (referred as Pdots/Ce6@lipid-Gd-DOTA micelles) for combined magnetic resonance imaging (MRI)/photoacoustic imaging (PAI) and photodynamic (PDT)/photothermal (PTT) dual-modal therapy that induced by a single laser to achieve enhanced cancer therapeutic efficiency. The Pdots/Ce6@lipid-Gd-DOTA micelles with excellent water dispersibility were comprised of a core with poly[2,6-(4,4-bis-(2-ethylhexyl)-4H-cyclopenta[2,1-b;3,4-b']-dithiophene)-alt-4,7-(2,1,3-benzo-thiadiazole)] dots (Pdots) and Ce6 molecules inside, and a lipid-PEG outlayer conjugated with gadolinium-1,4,7,10-tetraacetic acid. The prepared Pdots/Ce6@lipid-Gd-DOTA micelles exhibited extremely low cytotoxicity, and had excellent MR- and PA-imaging contrast-enhancement ability, which could synchronously offer anatomical information and morphological information of tumors. Moreover, both Pdots and Ce6 photosensitizer, encapsulated inside the lipid-Gd-DOTA micelles, exhibited high NIR absorption at 670 nm and were applied to combine photothermal and photodynamic therapy simultaneously to achieve enhanced synergistic cancer therapeutic efficiency both in vitro and in vivo. In summary, our studies demonstrated that Pdots/Ce6@lipid-Gd-DOTA micelles with multi-diagnosis modalities and simultaneous dual-modal photo-therapy functions might be a potential interesting theranostic platform for tumor treatment.


[The neurobiology of slow-wave sleep].
In the two last years my lectures were addressed to the biological bases of wakefulness and REM sleep. The present lecture is focused on slow wave sleep, which corresponds to stages 3 and 4 in humans. These two sleep stages both present high voltage slow waves in the EEG that belong to the delta band (less than 3 Hz). Slow wave sleep usually lasts between 70 and 90 minutes in normal individuals, and takes place during the first hours of the night, as though our organism was making sure we got this essential sleep. Slow wave sleep is: a) the first sleep stage to recuperate after sleep deprivation, b) the stage with the most constant length even in individuals who have very different sleep habits, and c) the sleep stage that remains constant during experiments of gradual sleep reduction for eight-hour sleepers. This sleep stage is the one in which growth hormone is released and it essential for physical and intellectual efficiency and normal behavior in young adult individuals. Slow wave sleep is remarkably reduced in old people. What brain structures are responsible for the bioelectric and behavioral events of the slow waves sleep? Both the cerebral cortex and thalamus are indispensable for the existence of the slow waves EEG characteristic to this stage. Other brain structures participate in slow wave sleep organization; these include the basal forebrain, the oral pontine reticular nucleus, the deep cerebellar nuclei and the solitary tract nucleus. In this presentation I consider the most relevant functions of these structures as well as their anatomical connections, mainly with the neuronal networks responsible for other stages of the sleep-wakefulness cycle.


Beliefs, endorsement and application of homeopathy disclosed: a survey among ambulatory care physicians.
Explanation models for the effectiveness of homeopathy are not supported by natural sciences and the aggregated evidence from clinical trials is unconvincing. From this standpoint, placebo effects seem the most obvious explanation for the therapeutic effects experienced in homeopathy. Still, many physicians continue to prescribe homeopathic treatments. Whether physicians who prescribe homeopathic treatments aim to achieve placebo effects or actually believe in specific effects is poorly understood. However, this distinction has important educational and ethical implications. Therefore, we aimed to describe the use of homeopathy among physicians working in outpatient care, factors associated with prescribing homeopathy, and the therapeutic intentions and attitudes involved. All physicians working in outpatient care in the Swiss Canton of Zurich in the year 2015 (n = 4072) were approached. Outcomes of the study were: association of prescribing homeopathy with medical specialties (odds ratios [OR] and 95% confidence intervals [95% CI] from multivariable logistic regression); intentions behind prescriptions (to induce specific or nonspecific/placebo effects); level of agreement with specific attitudes; and views towards homeopathy including explanatory models, rating of homeopathy's evidence base, the endorsement of indications, and reimbursement of homeopathic treatment by statutory health insurance providers. The participation rate was 38%, mean age 54 years, 61% male, and 40% specialised in general internal medicine. Homeopathy was prescribed at least once a year by 23% of the respondents. Medical specialisations associated with prescribing homeopathy were: no medical specialisation (OR 3.9; 95% CI 1.7-9.0), specialisation in paediatrics (OR 3.8 95% CI 1.8-8.0) and gynaecology/obstetrics (OR 3.1 95% CI 1.5-6.7). Among prescribers, only 50% clearly intended to induce specific homeopathic effects, only 27% strongly adhered to homeopathic prescription doctrines, and only 23% thought there was scientific evidence to prove homeopathy's effectiveness. Seeing homeopathy as a way to induce placebo effects had the strongest endorsement among prescribers and non-prescribers of homeopathy (63% and 74% endorsement respectively). Reimbursement of homeopathic remedies by statutory health insurance was rejected by 61% of all respondents. Medical specialties use homeopathy with significantly varying frequency and only half of the prescribers clearly intend to achieve specific effects. Moreover, the majority of prescribers acknowledge that effectiveness is unproven and give little importance to traditional principles behind homeopathy. Medical specialties and associated patient demands but also physicians' openness towards placebo interventions may play a role in homeopathy prescriptions. Education should therefore address not only the evidence base of homeopathy, but also ethical dilemmas with placebo interventions.


Comorbid mental disorders in children and adolescents with attention-deficit/hyperactivity disorder in a large nationwide study.
The present study aimed at identifying the full range of mental disorders comorbid to attention-deficit/hyperactivity disorder (ADHD) in children and adolescents (age 4-17) diagnosed in Danish psychiatric hospitals between 1995 and 2010. A total of 14,825 patients were included in the study and comorbid disorders diagnosed concurrent with ADHD were identified. Associations of comorbid disorders with sex, age, and other mental disorders were investigated by logistic regression analysis. In the total sample, 52.0 % of the patients had at least one psychiatric disorder comorbid to ADHD and 26.2 % had two or more comorbid disorders. The most frequent comorbid disorders were disorders of conduct (16.5 %), specific developmental disorders of language, learning and motor development (15.4 %), autism spectrum disorders (12.4 %), and intellectual disability (7.9 %). Male sex was generally associated with an increased risk for neuropsychiatric disorders while female sex was associated more frequently with internalizing disorders. The analysis of associations between the various comorbid disorders identified several clusters highlighting the differential developmental trajectories seen in patients with ADHD. The study provides evidence that comorbidity with mental disorders is developmentally sensitive. Furthermore, the study shows that particular attention should be given to patients with neurodevelopmental disorders such as autism and intellectual disability in future longitudinal analyses. These disorders are very frequent in patients with ADHD, and the affected patients might follow a different course than patients without these disorders.


Stereoselective skin anti-photoaging properties of ginsenoside Rg3 in UV-B-irradiated keratinocytes.
Ginsenosides are major bioactive constituents that are responsible for the diverse pharmacological activities of ginseng. This work aimed to assess the skin anti-photoaging activities of the two stereoisomeric forms of ginsenoside Rg3, 20(S)-Rg3 and 20(R)-Rg3. When the two Rg3 stereoisomers were added to cultured human keratinocyte HaCaT cells prior to irradiation with 70 mJ/cm(2) UV-B, 20(S)-Rg3, but not 20(R)-Rg3, decreased the UV-B-induced intracellular reactive oxygen species (ROS) levels in a concentration-dependent manner, as detected by both fluorometric and confocal microscopic analyses. Likewise, 20(S)-Rg3, but not 20(R)-Rg3, decreased the UV-B-induced ROS levels in human dermal fibroblast cells. Both stereoisomers were unable to modulate the nitric oxide levels in HaCaT cells under UV-B irradiation, and induced no cytotoxicity in cultured keratinocytes and fibroblasts. 20(S)-Rg3 suppressed the UV-B-induced matrix metalloproteinase (MMP)-2 activities in HaCaT cells. Taken together, these results indicate that 20(S)-Rg3 possesses both ROS-scavenging and MMP-2 inhibitory activities, while 20(R)-Rg3 possesses neither activity. These findings imply that ginsenoside Rg3 stereoselectively demonstrates skin anti-photoaging activities.


Supervisor volume affects oncological outcomes of trainees performing open radical prostatectomy.
The relationship between biochemical failure (BF) rate and surgeon experience following open radical prostatectomy (ORP) has been well established, but BF when ORP is performed by urology trainees who are supervised by urologists of differing volume has not. We aimed to compare the oncological outcomes from ORP when a urology trainee as primary operator and is supervised by a high- or low-volume consultant urologist. Using a centralized whole of population dataset, created through the Victorian Radical Prostatectomy Registry, patients were classified as either those where a consultant was the primary operator, a urology trainee was the primary operator and supervised by a high-volume consultant or those where a urology trainee was supervised by a low-volume consultant. BF- and prostate cancer (PCa)-specific mortality was compared between these latter two groups and the consultant-only group. We found BF- and PCa-specific mortality rate to be poorer when ORP was performed by a urology trainee supervised by a low-volume consultant compared with consultant-led surgery (hazard ratio (HR) = 1.33, P = 0.022; subhazard ratio (SHR) = 2.31, P = 0.010, respectively). When a urology trainee, as primary operator, was supervised by a high-volume consultant, there was no statistical difference in BF- or PCa-specific mortality rate following ORP compared with consultant-led surgery (HR = 1.19, P = 0.234; SHR = 1.53, P = 0.346, respectively). There was a trend evident with decreasing supervisor volume leading to worse oncological and mortality outcomes for trainee-led cases. This study demonstrates the value of high-volume and fellowship-trained urologists in performing and teaching ORP. As outcomes are increasingly scrutinized with audits, the best strategy for clinicians to maintain standards and optimal patient outcomes is to understand these elements and direct trainees to appropriate centres for training and fellowships.


Extracorporeal support, during and after lung transplantation: the history of an idea.
During recent years, continuous technological innovation has provoked an increase of extracorporeal life support (ECLS) use for perioperative cardiopulmonary support in lung transplantation. Initial results were disappointing, due to ECLS-specific complications and high surgical risk of the supported patients. However, the combination of improved patient management, multidisciplinary team work and standardization of ECLS protocols has recently yielded excellent results in several case series from high-volume transplant centres. Therein, it was demonstrated that, although the prevalence of complications remains higher in supported patients, there may be no difference in long-term graft function between supported and non-supported patients. These results are important, because most of the patients who require ECLS support in lung transplantation are young and have no other chance to survive, but to be transplanted. Moreover, there is no device for "bridging to destination" therapy in lung transplantation. Of note, the evidence in favour of ECLS support in lung transplantation was never validated by randomized controlled trials, but by everyday experience at the patient bed-side. Here, we review the state-of-the-art ECLS evidence for intraoperative and postoperative cardiopulmonary support in lung transplantation.


Evidence for FUS6 as a component of the nuclear-localized COP9 complex in Arabidopsis.
The pleiotropic CONSTITUTIVE PHOTOMORPHOGENIC (COP), DEETIOLATED (DET), and FUSCA (FUS) loci are essential regulatory genes involved in the light control of seedling developmental patterns in Arabidopsis. Although COP1, DET1, COP9, and FUS6 (also called COP11) have been cloned, their biochemical activities and interactions remain elusive. We have recently suggested that multiple pleiotropic COP, DET, and FUS genes may encode subunits of a large regulatory complex. In this study, we generated specific antibodies against Arabidopsis FUS6 and show that accumulation of both COP9 and FUS6 is coordinated in the pleiotropic cop, det, and fus mutant backgrounds and in wild-type plants throughout development. Both COP9 and FUS6 cofractionated into identical high molecular mass fractions in an analytical gel filtration assay, and neither was found in its monomeric form. Moreover, antibodies raised against either COP9 or FUS6 selectively coimmunoprecipitated both proteins. We have also developed an Arabidopsis protoplast immunolocalization assay and demonstrated that the COP9 complex is localized in the nucleus and that its nuclear localization is not affected by light conditions or tissue types. The integrated genetic and biochemical results strongly support the conclusion that both COP9 and FUS6 are components of the nuclear-localized COP9 complex. Therefore, we have provided the strongest evidence for the conclusion that at least some of the pleiotropic COP, DET, and FUS loci act in the same signaling pathway.


Association of apixaban therapy and prothrombin time in patients with atrial fibrillation.
This study evaluated whether measuring prothrombin time (PT) using particular reagents of interest predicted apixaban-associated anticoagulant activity in Japanese patients with non-valvular atrial fibrillation (NVAF). METHODS AND RESULTS: Two reagents, Shinplastin Excel S and Coagpia PT-N, were used to evaluate PT under apixaban therapy. From June 2013 to February 2014, 103 NVAF patients were recruited, and PT was measured at 3 time points: (1) anytime in the outpatient clinic, (2) at peak, and (3) at trough. In spike-in experiments using pooled citrated normal human platelet-poor plasma with these PT reagents, apixaban prolonged PT values in a concentration-dependent manner. PT values significantly correlated between both reagents (r=0.97) in outpatients. PT values in outpatients taking 5-mg apixaban bid were significantly prolonged and had wide inter- and intraindividual variability. Peak values were significantly higher than trough values, with both values higher than normal. The dose change of apixaban from 5 mg bid to 2.5 mg bid in outpatients halved the degree of PT prolongation in each NVAF patient. The PT value measured by these specific reagents can predict apixaban-associated anticoagulant activity, although there is significant interpatient variability.


What can we learn from the five-year African swine fever epidemic in Asia?
Today's global swine industry is exposed to the unprecedented threat of African swine fever (ASF). Asia, the site of the most recent epidemics, could serve as a huge viral reservoir for the rest of the world given the severity of the damage, the huge swine industry, and the high volume of trade with other countries around the world. As the majority of ASF notifications in Asia today originate from pig farms, the movement of live pigs and associated pork products are considered critical control points for disease management. Particularly, small-scale or backyard farms with low biosecurity levels are considered major risk factors. Meanwhile, wild boars account for most notified cases in some countries and regions, which makes the epidemiological scenario different from that in other Asian countries. As such, the current epidemic situation and higher risk factors differ widely between these countries. A variety of studies on ASF control have been conducted and many valuable insights have been obtained in Asia; nevertheless, the overall picture of the epidemic is still unclear. The purpose of this review is to provide an accurate picture of the epidemic situation across Asia, focusing on each subregion to comprehensively explain the disease outbreak. The knowledge gained from the ASF epidemics experienced in Asia over the past 5 years would be useful for disease control in areas that are already infected, such as Europe, as well as for non-affected areas to address preventive measures. To this end, the review includes two aspects: a descriptive analytical review based on publicly available databases showing overall epidemic trends, and an individualized review at the subregional level based on the available literature.


Avoiding ureteral injury during total vaginal hysterectomy.
One third of ureteral injuries in gynecologic surgery occur during vaginal hysterectomy. The current techniques of dissecting the ureters in abdominal hysterectomy should carry over into vaginal operations. We studied 30 consecutive patients having vaginal hysterectomy by a surgical procedure allowing routine vaginal ureteral dissection.


New trends in anti-atherosclerotic agents.
New approaches to atherosclerosis-related diseases include novel uses of proven treatments and development of innovative agents. Several commonly used cardiovascular drugs such as dihydropyridine calcium antagonists, ACE inhibitors containing the sulphydryl group, or highly lipophilic beta-blockers have some anti-atherosclerotic activities. Moreover, new clinical trials suggesting that additional reduction of low-density lipoprotein cholesterol levels with statin therapy results in additional benefit in coronary heart disease prevention. Notably, new cholesterol transport or bile acid transport inhibitors have been found to produce significant reductions in intestinal cholesterol absorption and experimental atherosclerosis. Inhibitors of acyl coenzyme A:cholesterol acyltransferase, which can reduce cholesterol storage in macrophages and in arterial lesions, have also been developed. Finally, newer therapeutical strategies against atherogenesis may include the use of antioxidants and cholestyramine during pregnancy or the development of metalloproteinase inhibitors.


A randomized phase 2 study of lenalidomide therapy for patients with relapsed or relapsed and refractory multiple myeloma.
This multicenter, open-label, randomized phase 2 study evaluated 2 dose regimens of lenalidomide for relapsed, refractory myeloma. Seventy patients were randomized to receive either 30 mg once-daily or 15 mg twice-daily oral lenalidomide for 21 days of every 28-day cycle. Patients with progressive or stable disease after 2 cycles received dexamethasone. Analysis of the first 70 patients showed increased grade 3/4 myelo-suppression in patients receiving 15 mg twice daily (41% versus 13%, P = .03). An additional 32 patients received 30 mg once daily. Responses were evaluated according to European Group for Blood and Marrow Transplantation (EBMT) criteria. Overall response rate (complete, partial, or minor) to lenalidomide alone was 25% (24% for once-daily and 29% for twice-daily lenalidomide). Median overall survival in 30-mg once-daily and twice-daily groups was 28 and 27 months, respectively. Median progression-free survival was 7.7 months on once-daily versus 3.9 months on twice-daily lenalidomide (P = .2). Dexamethasone was added in 68 patients and 29% responded. Time to first occurrence of clinically significant grade 3/4 myelosuppression was shorter in the twice-daily group (1.8 vs 5.5 months, P = .05). Significant peripheral neuropathy and deep vein thrombosis each occurred in only 3%. Lenalidomide is active and well tolerated in relapsed, refractory myeloma, with the 30-mg once-daily regimen providing the basis for future studies as monotherapy and with dexamethasone.


catena-Poly[bis-(μ(4)-adipato-1:2:1':2'κO:O:O:O)bis-(N,N-dimethyl-formamide)-1κO,2κO-dicopper(II)].
In the title polymeric complex, [Cu(2)(C(6)H(8)O(4))(2)(C(3)H(7)NO)(2)](n), the carboxyl-ate groups of the approximately U-shaped adipate dianion each bridge a pair of inversion-related, DMF-coordinated copper(II) atoms, generating a ribbon motif that runs along the b axis. The geometry of the copper(II) atom is distorted square-pyramidal; the apical site is occupied by the O atom of the DMF mol-ecule whereas the four basal sites are occupied by carboxyl-ate O atoms.


Clearance of mucus from endotracheal tubes during intratracheal pulmonary ventilation.
Intratracheal pulmonary ventilation (ITPV) is a form of tracheal gas insufflation in which all gas emerges in a cephalad direction from the tip of a reverse-thrust catheter positioned within an endotracheal tube. In vitro experiments have shown that this rapid gas flow, with 5 ml/h of normal saline added to the gas flow, continuously removes tracheal secretions from within the endotracheal tube. The authors evaluated its effectiveness to remove mucus in long-term studies in sheep. Fourteen healthy sheep were tracheally intubated and ventilated for 3 days with ITPV or with volume-controlled ventilation. Measurements were made of the total amount of secretions within the endotracheal tubes (weight gain), the protein content within the endotracheal tubes, and the increase in resistance to constant air flow. The structure of the airways was examined grossly and histologically. Three additional sheep were ventilated for 24 h with ITPV, and Evans Blue dye was added to the saline to assess the distribution of the infused saline. There was significantly less mucus in endotracheal tubes of sheep ventilated with ITPV than with conventional ventilation, as shown by minimal weight gain (0.70 +/- 0.14 g vs. 2.44 +/- 0.81 g; P < 0.001), lower protein content (14.09 +/- 10.79 mg vs. 294.99 +/- 153.06 mg; P < 0.001), and lower resistance to constant air flow (6.15 +/- 0.54 cm H2O x 1(-1) x s(-1) vs. 15.34 +/- 5.28 cm H2O x 1(-1) x s(-1); P < 0.001). Results of gross and histological examinations of the tracheas of animals in both groups were similar, and the tracheas were well preserved. More than 95% of the instilled saline was recovered during ITPV. Only traces of Evans Blue dye were found near the tip of the endotracheal tubes. Intratracheal pulmonary ventilation makes it possible to keep the endotracheal tubes of sheep ventilated for 3 days free of mucus without suctioning.


Diffusing colloidal probes of cell surfaces.
Measurements and analyses are reported to quantify dynamic and equilibrium interactions between colloidal particles and live cell surfaces using dark field video microscopy. Two-dimensional trajectories of micron-sized polyethylene glycol (PEG)-coated silica colloids relative to adherent epithelial breast cancer cell perimeters are determined allowing measurement of position dependent diffusivities and interaction potentials. PEG was chosen as the material system of interest to assess non-specific interactions with cell surfaces and establishes a basis for investigation of specific interactions in future studies. Analysis of measured potential energies on cell surfaces reveals the spatial dependence in cell topography. With the measured cell topography and models for particle-cell surface hydrodynamic interactions, excellent agreement is obtained between theoretical and measured colloidal transport on cell surfaces. Quantitative analyses of association lifetimes showed that PEG coatings act to stabilize colloids above the cell surface through net repulsive, steric interactions. Our results demonstrate a self-consistent analysis of diffusing colloidal probe interactions due to conservative and non-conservative forces to characterize biophysical cell surface properties.


Relating Peanut Rx Risk Factors to Epidemics of Early and Late Leaf Spot of Peanut.
Previous research has demonstrated the efficacy of prescription fungicide programs, based upon Peanut Rx, to reduce combined effects of early leaf spot (ELS), caused by Passalora arachidicola (Cercospora arachidicola), and late leaf spot (LLS), caused by Nothopassalora personata (syn. Cercosporidium personatum), but the potential of Peanut Rx to predict each disease has never been formally evaluated. From 2010 to 2016, non-fungicide-treated peanut plots in Georgia and Florida were sampled to monitor the development of ELS and LLS. This resulted in 168 cases (unique combinations of Peanut Rx risk factors) with associated total leaf spot risk points ranging from 40 to 100. Defoliation ranged from 13.9 to 100%, and increased significantly with increasing total risk points (conditional R2 = 0.56; P < 0.001). Leaf spot onset (time in days after planting [DAP] when either leaf spot reached 1% lesion incidence), ELS onset, and LLS onset ranged from 29 to 140, 29 to 142, and 50 to 143 DAP, respectively, and decreased significantly with increasing risk points. Standardized AUDPC of ELS was significantly affected by risk points (conditional R2 = 0.53, P < 0.001), but not for LLS. After removing redundant Peanut Rx factors, planting date, rotation, historical leaf spot prevalence, cultivar, and field history were used as fixed effects in mixed effect regression models to evaluate their contribution to leaf spot, ELS or LLS prediction. Results from mixed effects regression confirmed that the selected Peanut Rx risk factors contributed to the variability of at least one measurement of development of combined or separate epidemics of ELS and LLS, but not all factors affected ELS and LLS equally. Historical leaf spot prevalence, a new potential preplant risk factor, was a consistent predictor of the dominant disease(s) observed in the field. Results presented here demonstrate that Peanut Rx is a very effective tool for predicting leaf spot onset regardless of which leaf spot is predominant, but also suggest that associated risk does not reflect the same development for each disease. These data will be useful for refining thresholds for differentiating high, moderate, and low risk fields, and reevaluating the timing of fungicide applications in reduced input programs with respect to disease onset.


An LC-MS-based chemical and analytical method for targeted metabolite quantification in the model cyanobacterium Synechococcus sp. PCC 7002.
Herein, we detail the development of a method for the chemical isolation and tandem LC-MS/MS quantification of a targeted subset of internal metabolites from cyanobacteria. We illustrate the selection of target compounds; requirements for and optimization of mass spectral detection channels, screening, and optimization of chromatography; and development of a sampling protocol that seeks to achieve complete, representative, and stable metabolite extraction on the seconds time scale. Several key factors influencing the separation by reversed-phase ion pairing chromatography, specifically the hydrophobicity of the sample matrix and sensitivity to mobile phase acidity, are identified and resolved. We illustrate this methodology with an example from the autofermentative metabolism in the model cyanobacterium Synechococcus sp. PCC 7002, for which intracellular levels of 25 metabolites were monitored over 48 h, including intermediates in central carbon metabolism together with those involved in the cellular energy charge and redox poise. Upon removal of alternative reductant sinks (nitrate), anoxia induces autofermentation of carbohydrates with a parallel rise in the intracellular pyridine nucleotide redox poise that is specific to NAD(H) and alongside a gradual decline in the adenylate energy charge. This LC-MS/MS-based method provides for accurate time-resolved quantification of multiple metabolites in parallel, thus enabling experimental verification of the active metabolic pathways.


Prevalence of necrotizing ulcerative gingivitis and associated factors in Koranic boarding schools in Senegal.
Necrotizing ulcerative gingivitis is the most common clinical syndrome preceding noma. It is found in developing countries and in malnourished children and especially in deprived groups such as children at Koranic boarding schools. The objective of this study was to determine the prevalence of necrotizing ulcerative gingivitis and factors associated with its occurrence in a boarding school population. This was a cross-sectional study of children in Koranic boarding schools in the city of Touba, Senegal. A multistage sampling strategy was used and 8 out of 17 schools were selected. The variables collected were gender, age, oral hygiene habits, duration of residence, presence of ulcerative gingivitis and plaque, and gingival bleeding index. A logistic regression analysis with R software using the manual procedure down was used to identify factors associated with the dependent variables. There were 501 participants and boys made up 92% of the study group. The mean age was 9.3 (sd 4.0) years. The mean of duration residence was 3.4 (sd 1.5) years. The prevalence of necrotizing ulcerative gingivitis was 37% and 81% of children did not use a toothbrush or a chewing-stick. The length of residence, school size, hygiene habits and plaque and bleeding indices were significantly associated with necrotizing gingivitis after adjustment for other variables. It is necessary to develop oral hygiene programs, to establish policies to manage the oral health of children and to improve health and nutrition at Koranic boarding-schools.


Paediatric pneumonia or empyema and prior antibiotic use in primary care: a case-control study.
To investigate the association between hospital presentation for paediatric pneumonia or empyema and prior antibiotic use for respiratory tract infection (RTI). Case-control study of children aged 6 months to 16 years presenting to hospital with radiographic evidence of pneumonia or empyema and a history of general practitioner (GP) consultation for the index illness. Cases were recruited from seven hospitals in South Wales between October 2008 and December 2009. Controls were children from the same age group who were diagnosed with an uncomplicated RTI in general practice in the same area and at a similar time of year. Primary data were collected from carers by a self-complete questionnaire, with a subsample compared against general practice records. We recruited 89 eligible cases and 166 eligible controls. Cases were less likely than controls to have been prescribed antibiotics at the first GP consultation for the index illness [odds ratio (OR) 0.53; 95% confidence interval (95% CI) 0.31-0.90]. Stratified analyses revealed that this association was limited to children who consulted a GP <3 days after illness onset (OR 0.23; 95% CI 0.10-0.50). Cases were also less likely to have taken antibiotics before the date of index hospital presentation, but this finding was not statistically significant after adjustment for confounding factors (adjusted OR 0.84; 95% CI 0.47-1.49). Antibiotics prescribed at the first GP consultation for an RTI may protect against subsequent hospital presentation for pneumonia or empyema in some children. Given the strong rationale against unnecessary antibiotic prescribing, further research is needed to identify which children are most likely to benefit from early antibiotic treatment.


Megaesophagus and pneumonia associated with Mycobacterium chelonei. A case report and a literature review.
The case of a 37-year-old woman who developed a subacute, bilateral, noncavitary pneumonia 5 years after a colon interposition esophagoplasty is presented. Mycobacterium chelonei, subspecies abscessus, was assigned a pathogenic role based on the findings of (1) a clinical and roentgenographic picture consistent with tuberculosis, (2) sputum smears showing acid-fast bacilli, (3) repeated sputum cultures yielding heavy growths of Mycobacterium chelonei, subspecies abscessus, and (4) a 12-mm by 12 mm-skin test response to homologous antigen (purified protein derivative-CL) with no response to an equivalent dose of purified protein derivative-S. The patient recovered fully without significant antituberculous chemotherapy. A survey of the literature revealed 11 similar case reports featuring a documented association between megaesophagus and pulmonary infection with rapidly growing mycobacteria.


Effect of experimental silane-based primers with various contents of 2-hydroxyethyl methacrylate on the bond strength of orthodontic adhesives.
To evaluate in vitro the effect of different concentrations of 2-hydroxyethyl methacrylate (HEMA) in experimental silane-based primers on shear bond strength of orthodontic adhesives. Different volume percentages of HEMA were tested in four experimental silane-based primer solutions (additions of HEMA: 0, 5.0 vol%, 25.0 vol% and 50.0 vol%). An experimental silane blend (primer) of 1.0 vol% 3-isocyanatopropyltrimethoxysilane (ICMS) + 0.5% bis-1,2-(triethoxysilyl) ethane (BTSE) was prepared and used. The experimental primers together with the control group were applied onto acid-etched premolars for attachment of orthodontic brackets. After artificial aging by thermocycling the shear-bond strength was measured. The fractured surfaces of all specimens were examined under scanning electron microscopy (SEM) to evaluate the failure mode on the enamel surface. The experimental primers showed the highest shear-bond strength of 21.15 MPa (SD ± 2.70 MPa) and with 25 vol% showed a highly significant increase (P < 0.05) in bond strength. The SEM images showed full penetration of adhesive agents when using silane-based primers. In addition, the SEM images suggested that the predominant failure type was not necessarily the same as for the failure propagation. This preliminary study suggested that nonacidic silane-based primers with HEMA addition might be an alternative to for use as adhesion promoting primers.


Multi-trait Genomic Selection Methods for Crop Improvement.
Plant breeders make selection decisions based on multiple traits, such as yield, plant height, flowering time, and disease resistance. A commonly used approach in multi-trait genomic selection is index selection, which assigns weights to different traits relative to their economic importance. However, classical index selection only optimizes genetic gain in the next generation, requires some experimentation to find weights that lead to desired outcomes, and has difficulty optimizing nonlinear breeding objectives. Multi-objective optimization has also been used to identify the Pareto frontier of selection decisions, which represents different trade-offs across multiple traits. We propose a new approach, which maximizes certain traits while keeping others within desirable ranges. Optimal selection decisions are made using a new version of the look-ahead selection (LAS) algorithm, which was recently proposed for single-trait genomic selection, and achieved superior performance with respect to other state-of-the-art selection methods. To demonstrate the effectiveness of the new method, a case study is developed using a realistic data set where our method is compared with conventional index selection. Results suggest that the multi-trait LAS is more effective at balancing multiple traits compared with index selection.


Dependency of codon usage on protein sequence patterns: a statistical study.
Codon degeneracy and codon usage by organisms is an interesting and challenging problem. Researchers demonstrated the relation between codon usage and various functions or properties of genes and proteins, such as gene regulation, translation rate, translation efficiency, mRNA stability, splicing, and protein domains. Researchers usually represent segments of proteins responsible for specific functions or structures in a family of proteins as sequence patterns or motifs. We asked the question if organisms use the same codons in pattern segments as compared to the rest of the sequence. We used the likelihood ratio test, Pearson's chi-squared test, and mutual information to compare these two codon usages. We showed that codon usage, in segments of genes that code for a given pattern or motif in a group of proteins, varied from the rest of the gene. The codon usage in these segments was not random. Amino acids with larger number of codons used more specific codon ratios in these segments. We studied the number of amino acids in the pattern (pattern length). As patterns got longer, there was a slight decrease in the fraction of patterns with significant different codon usage in the pattern region as compared to codon usage in the gene region. We defined a measure of specificity of protein patterns, and studied its relation to the codon usage. The difference in the codon usage between pattern region and gene region, was less for the patterns with higher specificity. We provided a hypothesis that there are segments on genes that affect the codon usage and thus influence protein translation speed, and these regions are the regions that code protein pattern regions.


Segmentally variable genes: a new perspective on adaptation.
Genomic sequence variation is the hallmark of life and is key to understanding diversity and adaptation among the numerous microorganisms on earth. Analysis of the sequenced microbial genomes suggests that genes are evolving at many different rates. We have attempted to derive a new classification of genes into three broad categories: lineage-specific genes that evolve rapidly and appear unique to individual species or strains; highly conserved genes that frequently perform housekeeping functions; and partially variable genes that contain highly variable regions, at least 70 amino acids long, interspersed among well-conserved regions. The latter we term segmentally variable genes (SVGs), and we suggest that they are especially interesting targets for biochemical studies. Among these genes are ones necessary to deal with the environment, including genes involved in host-pathogen interactions, defense mechanisms, and intracellular responses to internal and environmental changes. For the most part, the detailed function of these variable regions remains unknown. We propose that they are likely to perform important binding functions responsible for protein-protein, protein-nucleic acid, or protein-small molecule interactions. Discerning their function and identifying their binding partners may offer biologists new insights into the basic mechanisms of adaptation, context-dependent evolution, and the interaction between microbes and their environment.


Self-injury in psychiatric in-patients.
Suicide and self-injury in-patients were identified on the basis of a retrospective content analysis of special incidence reports completed the preceding year at an urban state psychiatric hospital. Select clinical and biodemographic variables were then examined, and in order to determine the importance of these variables in the prediction of incident severity, a multiple regression analysis was performed. Schizophrenic patients were found to be significantly over-represented among both the self-injury and suicide patients.


The Role of B Cells in Carriage and Clearance of Mycoplasma pneumoniae From the Respiratory Tract of Mice.
Carriage of Mycoplasma pneumoniae (Mp) in the nasopharynx is considered a prerequisite for pulmonary infection. It is interesting to note that Mp carriage is also detected after infection. Although B cells are known to be involved in pulmonary Mp clearance, their role in Mp carriage is unknown. In this study, we show in a mouse model that Mp persists in the nose after pulmonary infection, similar to humans. Infection of mice enhanced Mp-specific immunoglobulin (Ig) M and IgG levels in serum and bronchoalveolar lavage fluid. However, nasal washes only contained elevated Mp-specific IgA. These differences in Ig compartmentalization correlated with differences in Mp-specific B cell responses between nose- and lung-draining lymphoid tissues. Moreover, transferred Mp-specific serum Igs had no effect on nasal carriage in B cell-deficient μMT mice, whereas this enabled μMT mice to clear pulmonary Mp infection. We report the first evidence that humoral immunity is limited in clearing Mp from the upper respiratory tract.


Changes in subjective experience elicited by direct stimulation of the human orbitofrontal cortex.
We applied direct cortical stimulation (DCS) to the orbitofrontal cortex (OFC) in neurosurgical patients implanted with intracranial electrodes to probe, with high anatomic precision, the causal link between the OFC and human subjective experience. We administered 272 instances of DCS at 172 OFC sites in 22 patients with intractable focal epilepsy (from 2011 to 2017), none of whom had seizures originating from the OFC. Our observations revealed a rich variety of affective, olfactory, gustatory, and somatosensory changes in the subjective domain. Elicited experiences were largely neutral or negatively valenced (e.g., aversive smells and tastes, sadness, and anger). Evidence was found for preferential left lateralization of negatively valenced experiences and strong right lateralization of neutral effects. Moreover, most of the elicited effects were observed after stimulation of OFC tissue around the transverse orbital sulcus, and none were seen in the most anterior aspects of the OFC. Our study yielded 3 central findings: first, a dissociation between the "silent" anterior and nonsilent middle/posterior OFC where stimulation clearly elicits changes in subjective experience; second, evidence that the OFC might play a causal role in integrating affect and multimodal sensory experiences; and third, clear evidence for left lateralization of negatively valenced effects. Our findings provide important information for clinicians treating OFC injury or planning OFC resection and scientists seeking to understand the brain basis for the integration of sensation, cognition, and affect.


Lymphedema and employability - Review and results of a survey of Austrian experts.
Literature about lymphedema and its influence on the ability to work and employability is limited. The aim of the present study was to investigate the opinion of Austrian experts on factors influencing the ability to work and employability in patients suffering from lymphedema. A self-administered questionnaire consisting of 6 questions was sent to 12 Austrian lymphedema experts with 6 different specializations from May to August 2016. These experts were asked about suitable and unsuitable professions, the possible influence of lymphedema on the ability to work and employability as well as about existing and additional measures to improve the return to work. The reply rate was 100% (12 out of 12). All experts agreed that lymphedema can restrict the ability to work and employability. The leading reason for limited ability to work and employability was restricted mobility or function of the affected limb along with time-consuming therapeutic modalities, pain and psychological stress. The most suitable job named was teacher and the most unsuitable job named was cook. As easements for return to work, early rehabilitation, self-management, coping strategies, patient education, employer's goodwill and employer's cooperation were reported. Furthermore, experts stressed the need for an adjustment of the legal framework as well as low-barrier and more therapy offers. Adjusted work demands seem to be of greater importance to support the ability to work and employability than recommendations for specific job profiles alone. Experts suggest an adjustment of the legal framework for affected patients, claiming a right for early rehabilitation as well as for life-long therapy. Even though some clinically useful conclusions may be drawn from this article, further research in the field is warranted.


Stress and Obesity.
Many pathways connect stress and obesity, two highly prevalent problems facing society today. First, stress interferes with cognitive processes such as executive function and self-regulation. Second, stress can affect behavior by inducing overeating and consumption of foods that are high in calories, fat, or sugar; by decreasing physical activity; and by shortening sleep. Third, stress triggers physiological changes in the hypothalamic-pituitary-adrenal axis, reward processing in the brain, and possibly the gut microbiome. Finally, stress can stimulate production of biochemical hormones and peptides such as leptin, ghrelin, and neuropeptide Y. Obesity itself can be a stressful state due to the high prevalence of weight stigma. This article therefore traces the contribution of weight stigma to stress and obesogenic processes, ultimately describing a vicious cycle of stress to obesity to stigma to stress. Current obesity prevention efforts focus solely on eating and exercise; the evidence reviewed in this article points to stress as an important but currently overlooked public policy target.